Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma

Abstract

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5

Sarcomatoid renal cell carcinoma: biology, natural history and management

“…Of 139 patients with sRCC (74 receiving ipilimumab plus nivolumab and 65 receiving sunitinib), the median follow-up duration was 47.7 months and ORR after ipilimumab plus nivolumab or sunitinib administration was 60.8% vs 23.1% compared with 41.9% vs 29.4% in the remaining participants, respectively. Overall PDL1 expression was higher in patients with sRCCs than in other patients (51% vs 27.5%), and patients with sRCCs with ≥1% PDL1 expression treated with ipilimumab plus nivolumab had a longer median OS than those treated with sunitinib 173 . Overall, patients with sRCCs treated with ipilimumab plus nivolumab had improved median PFS (26.5 vs 5.1 months, P = 0.0093), complete response rates (18.9% vs 3.1%), partial response rates (41.9% vs 20.0%) and median OS (not reached vs 14.2 months, P = 0.0155) compared with those treated with sunitinib 173,174 .…”

“…Overall PDL1 expression was higher in patients with sRCCs than in other patients (51% vs 27.5%), and patients with sRCCs with ≥1% PDL1 expression treated with ipilimumab plus nivolumab had a longer median OS than those treated with sunitinib 173 . Overall, patients with sRCCs treated with ipilimumab plus nivolumab had improved median PFS (26.5 vs 5.1 months, P = 0.0093), complete response rates (18.9% vs 3.1%), partial response rates (41.9% vs 20.0%) and median OS (not reached vs 14.2 months, P = 0.0155) compared with those treated with sunitinib 173,174 . The 42-month overall survival probability was 50.1% (95% CI 37.9-61.2) with 175 .…”

“…A post hoc exploratory analysis of the CheckMate214 trial 172 , which originally assessed the anti-CTLA4 agent ipilimumab plus the anti-PDL1 agent nivolumab compared with single-agent anti-VEGF sunitinib in patients with intermediate-risk or poor-risk RCC, identified patients with sarcomatoid histology and measured efficacy and safety outcomes in this subpopulation 173 . Of 139 patients with sRCC (74 receiving ipilimumab plus nivolumab and 65 receiving sunitinib), the median follow-up duration was 47.7 months and ORR after ipilimumab plus nivolumab or sunitinib administration was 60.8% vs 23.1% compared with 41.9% vs 29.4% in the remaining participants, respectively.…”

“…The growing number and availability of immune checkpoint inhibitors such as anti-CTLA4, anti-PD1 and anti-PDL1 systemic agents in the setting of compelling data supporting higher expression of PD1 and PDL1 and greater infiltration of T reg cells in sRCCs than in non-sarcomatoid RCCs suggests that this signalling axis could be a critical therapeutic target. Future clinical trials should focus on therapies such as anti-CTLA4, anti-PDl, anti-PDL1 and combinations with targeted therapy agents that have been shown to augment the cytotoxic tumour immune microenvironment 99,122,168,169,173,[186][187][188][189] with the aim of improving progression and survival outcomes in patients with sRCCs.…”

Dual immune checkpoint inhibition in metastatic renal cell carcinoma

“…These results are only surpassed in the subgroup of sRCC patients with PD-L1 expression; ORR and CR rate were 69% and 22%, respectively; OS not reached versus 14.2 months with sun (hazard ratio 0.45) and PFS 26.5 versus 5.1 months (hazard ratio 0.54). 5 …”